Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][C@H:10]([NH:26]C(=O)OC(C)(C)C)[C:11](=[O:25])[N:12]([CH2:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][C:15]=3[CH3:24])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[NH2:26][C@H:10]1[CH2:9][O:8][C:7]2[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=2[N:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][C:15]=2[CH3:24])[C:11]1=[O:25]
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2c(Br)cccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](N)COc2c(Br)cccc21
Reaction time: 0.75 h

Procedure:
In a similar manner to that described for Example 89 Step 2 except the reaction was stirred 45 min., (S)-tert-butyl 9-bromo-5-((2-methylnaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (40 mg, 78.2 μmol) in DCM (2 mL) was cooled to 0° C. and treated with TFA (300 μl). After 45 min, the mixture was concentrated to dryness and the residue azeotroped with MeCN to afford (S)-3-amino-9-bromo-5-((2-methylnaphthalen-1-yl)methyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4 (5H)-one trifluoroacetate (41 mg), which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17].C(OC(O)C)C>C(OCC)C>[Cl:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4]([OH:5])=[N:17][CH:16]=[N:1]2)=[CH:7][CH:8]=1
Reactant: N=CN
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: CCOC(C)O
Solvent: CCOCC
Solvent: CC(=O)O
Product: Oc1ncnc2cc(Cl)ccc12
Temperature: 25 °C
Yield: 130.2 %

Procedure:
2-Amino-4-chloro-benzoic acid (1.00 g, 11.7 mmol, 1.0 eq.), formamidine acetate (3.64 mL, 35.0 mmol, 3 eq.), and ethoxyethanol (20 mL) were refluxed under nitrogen overnight. Cooled to rt. Added 25 mL of diethyl ether. Solids precipitated. Filtered off solids. Pumped under high vacuum to give 2.75 g of white solids as product. LCMS detects (M+H)+=181.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[C:15]2[CH:16]=[CH:17][C:18]([NH2:20])=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)=[O:8].Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:31]=2[C:32]([NH:34][CH2:35][C:36]#[CH:37])=[O:33])[C:26]([Cl:43])=[CH:25][N:24]=1>>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[C:15]2[CH:16]=[CH:17][C:18]([NH:20][C:23]3[N:28]=[C:27]([NH:29][C:30]4[C:31]([C:32](=[O:33])[NH:34][CH2:35][C:36]#[CH:37])=[CH:38][CH:39]=[CH:40][C:41]=4[F:42])[C:26]([Cl:43])=[CH:25][N:24]=3)=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)=[O:8]
Reactant: CN(C)CCCOC(=O)N1CCCOc2cc(N)ccc21
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OCCCN(C)C)ncc1Cl

Procedure:
3-[5-Chloro-4-(2-fluoro-6-prop-2-ynylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 3-dimethylamino-propyl ester was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 3-dimethylamino-propyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 1410. Product isolated as an orange foam (85 mg, 49%). LCMS (m/e) 596 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.47-9.36 (m, 1H), 9.25-9.14 (m, 1H), 9.05-8.94 (m, 1H), 8.19 (s, 1H), 7.58-7.40 (m, 3H), 7.33-7.22 (m, 1H), 7.15-7.04 (m, 1H), 6.97-6.89 (m, 1H), 4.14-3.80 (m, 6H), 3.65-3.39 (m, 2H), 3.13-3.08 (m, 1H), 2.21-1.99 (m, 8H), 1.97-1.82 (m, 2H), 1.62-1.48 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][O:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH3:24])(=[O:4])=[O:3].[H][H].[OH-].[Na+]>FC(F)(F)C(O)=O.O.[Pt]=O>[CH3:1][S:2]([CH2:5][CH2:6][O:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH3:24])(=[O:3])=[O:4]
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCOCCS(C)(=O)=O
Reactant: [H][H]
Agent: O=[Pt]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c(N)nc3c(c2n1CCOCCS(C)(=O)=O)CCCC3
Yield: 76.4 %

Procedure:
Solid platinum oxide (0.5) was added to a solution of 1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (0.9 g, 2.6 mmol) in trifluoroacetic acid (7 mL) in a Parr vessel. The vessel was placed on a shaker and then pressurized with hydrogen to 50 psi (3.4×105 Pa). Hydrogen was added periodically to maintain the pressure. After 55 hours the reaction mixture was purged with nitrogen and then filtered through a layer of CELITE filter agent. The filter cake was washed with dichloromethane (˜200 mL). The filtrate was concentrated under reduced pressure to provide an oil. The oil was dissolved in water (50 mL). The pH of the solution was adjusted to pH 12 by the addition of aqueous 50% sodium hydroxide and then the solution was extracted with dichloromethane (2×100 mL). The combined extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide crude product as a white foam. This material was recrystallized from ethyl acetate. The resulting off white plates were isolated by filtration, washed with ethyl acetate and dried under vacuum at 65° C. for 4 hours to provide 0.7 g of 1-{2-[2-(methylsulfonyl)ethoxy]ethyl}-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine, mp 173-175° C. 1H NMR (300 MHz, DMSO-d6) δ 5.65 (bs, 2H), 4.40 (t, J=5.0 Hz, 2H), 3.73 (t, J=5.6 Hz, 2H), 3.32 (t, J=5.6 Hz, 2H), 2.91 (m, 2H), 2.78 (s, 3H) 2.65 (m, 2H), 2.47 (s, 3H), 1.75 (m, 4H); MS (APCI) m/z 353 (M+
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([CH3:15])[C:5]=2[N:6]=1.NC1C=CC(C(OC)=O)=CC=1C.[Br:28]Br>CC(O)=O>[Br:28][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[C:7]([CH3:15])[C:5]=2[N:6]=1
Reactant: BrBr
Reactant: COC(=O)c1cc(C)c2nc(N)sc2c1
Agent: COC(=O)c1ccc(N)c(C)c1
Solvent: CC(=O)O
Product: COC(=O)c1cc(C)c2nc(Br)sc2c1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Methyl 2-amino-4-methyl-benzothiazole-6-carboxylate (I-16A). Into a 500-mL round-bottom flask was placed a solution of methyl 4-amino-3-methylbenzoate (4.00 g, 24.2 mmol, 1.00 equiv) and NaSCN (7.00 g, 86.4 mol, 3.57 equiv) in AcOH (90 mL) that was cooled to 0° C. This was followed by the addition of a solution of Br2 (3.9 g, 25 mmol, 1.0 equiv) in AcOH (25 mL) dropwise, maintaining at 0° C. over 20 min. The resulting solution was allowed to warm to RT on its own accord (over approximately 10 min.) and stirred for 48 hrs at RT. At this time, the solids of the reaction were filtered out. The resulting solution was diluted with 100 mL H2O. The pH value of the solution was adjusted to 8-9 with ammonia (using Whatman PH strip paper to monitor PH adjustment) which furnished an immediate precipitation. The solids were collected by filtration and washed once with ice cold MeOH (50 mL) to afford as a yellow solid. MS m/z 223.0 (M+11). 1H NMR (400 MHz, MeOH-d4) δ 8.17 (app d, J=1.0 Hz, 1H), 8.03 (br s, 2H, NH2), 7.68 (s, 1H), 3.82 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:14])[N:9]([CH2:11][CH:12]=[CH2:13])[CH2:10][C:6]=2[N:5]=[C:4]2[N:15]([CH2:18][CH2:19]Cl)[N:16]=[CH:17][C:3]=12.N12CCCN=C1CCCCC2.O>CN(C=O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:14])[N:9]([CH2:11][CH:12]=[CH2:13])[CH2:10][C:6]=2[N:5]=[C:4]2[N:15]([CH:18]=[CH2:19])[N:16]=[CH:17][C:3]=12
Reactant: C=CCN1Cc2nc3c(cnn3CCCl)c(N)c2C1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1Cc2nc3c(cnn3C=C)c(N)c2C1=O
Reaction time: 5 h
Yield: 80.8 %

Procedure:
A solution of 4-amino-1-(2-chloroethyl)-6,7-dihydro-6-(2-propenyl)pyrazolo[3.4-b]pyrrolo[3,4-e]pyridin-5(1H)-one (15.69 g.) in dry DMF (65 ml.) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (9.65 ml.). The mixture was heated to 110° under nitrogen with stirring for five hours. After cooling, the mixture was poured into water (400 ml.) and the product was extracted into dichloromethane. The extract was washed with brine, dried (Na2SO4) and evaporated at reduced pressure to afford a suspension of crude product in DMF. This was warmed to effect complete dissolution, and water (350 ml.) was added to precipitate the product. After cooling to 0° , the precipitated solid was collected by filtration, washed with water, and dried in vacuo at 50° . In this manner there was obtained 11.09 grams of 4-amino-6,7-dihydro6-(2-propenyl)-1-vinylpyrazolo[3,4-b]pyrrolo[3,4-e]pyridin-5(1H)-one as a light yellow solid: m.p. 190°-191°.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH:16]3[CH2:18][CH2:17]3)[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:19]([O:22][CH2:23][C:24]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[CH:26][C:25]=1[N:39]1[CH2:51][CH2:50][N:42]2[C:43]3[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=3[CH:49]=[C:41]2[C:40]1=[O:52])(=[O:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl>[C:19]([O:22][CH2:23][C:24]1[C:25]([N:39]2[CH2:51][CH2:50][N:42]3[C:43]4[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=4[CH:49]=[C:41]3[C:40]2=[O:52])=[CH:26][CH:27]=[CH:28][C:29]=1[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH:16]3[CH2:18][CH2:17]3)[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:21])[CH3:20]
Reactant: Cn1cc(Br)nc(Nc2cnn(C3CC3)c2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3cnn(C4CC4)c3)n2)cccc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
To a microwave tube equipped with a stirring bar, 114b (200 mg, 0.645 mmol), 114a (0.903 mmol), Pd(PPh3)4, Na2CO3 aqueous solution (1.0 N, 2.13 mL, 2.13 mmol), DME (2.0 mL) were added. The mixture was reacted in microwave at 135° C. for 15 min. DCM (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (MeOH:DCM=5:95) gave 2-(6-(1-cyclopropyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl acetate 114c, it was directly used in the next step.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[C:8]2O[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:12][C:7]2=[CH:6][CH:5]=1)([O-])=O.[CH3:19][OH:20].[CH:21]1C=CC=CC=1.C=O>[Ni].C(O)(=O)C>[CH3:8][N:9]([CH3:21])[C:4]1[N:1]=[C:19]2[O:20][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:12][C:7]2=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2nc(-c3ccccc3)oc2n1
Reactant: c1ccccc1
Reactant: CO
Agent: [Ni]
Agent: C=O
Solvent: CC(=O)O
Product: CN(C)c1ccc2nc(-c3ccccc3)oc2n1

Procedure:
5-Nitro-2-phenyloxazolo[ 5,4-b]pyridine (1.2 g.) in 75 ml. of methanol, 75 ml. of benzene, 5 ml. of acetic acid and 8 ml. of 37% formaldehyde solution was hydrogenated over 1.5 teaspoonsful of Raney nickel. The catalyst was removed by filtration and the filtrate was diluted with 10 ml. of water and basified with solid sodium bicarbonate. The mixture was concentrated to dryness. The residue was crystallized from ethyl acetate to give 5-dimethylamino-2-phenyloxazolo-[ 5,4-b]pyridine, m.p. 127°-129° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[CH2:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:47])[CH2:34][CH2:35][NH:36]C(OCC1C=CC=CC=1)=O)=[O:25])C1C=CC=CC=1.[C:48]([OH:51])(=[O:50])[CH3:49].[H][H].CCOCC>C(O)C.[C].[Pd]>[C:48]([OH:51])(=[O:50])[CH3:49].[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH2:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:47])[CH2:34][CH2:35][NH2:36])=[O:25]
Reactant: [H][H]
Reactant: O=C(CCNC(=O)OCc1ccccc1)NCCCCCNC(=O)Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CCO
Product: NCCC(=O)NCCCCCNC(=O)Cc1ccc(O)cc1O
Reaction time: 4 h

Procedure:
To a solution (20 ml) of 1-(2,4-dibenzyloxyphenylacetyl)amino-5-(3-benzyloxycarbonylaminopropionyl)aminopentane (440 mg) in ethanol are added 10 % palladiumcarbon (70 mg) and acetic acid (0.01 ml) and catalytic reduction is conducted in a hydrogen stream at room temperature under atmospheric pressure. After four hours, the catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. To the glass-like product obtained is added ether to digest into powder. The resulting product is filtered and dried to yield 1-(2,4-dihydroxyphenylacetyl)amino-5-(3-aminopropionyl)aminopentane acetate (209 mg).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[C:1]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1cccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)c1cccnc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
In a typical run, nicotinic acid (2.0 g, 16.2 mmol) was taken up in CH2Cl2 (20 mL) along with oxalyl chloride (1.4 mL, 16.2 mmol). After a few drops of DMF were added, the reaction mixture was stirred at room temperature until all the solids had dissolved and all gas evolution had ceased (1 h). This freshly prepared solution of the acid chloride was added dropwise at 0° C. to a solution containing tert-butyl 2-aminoethylcarbamate (2.6 g, 16.2 mmol) and Et3N (3.4 mL, 24.2 mmol) in CH2Cl2 (200 mL). The resulting reaction mixture was warmed to room temperature and stirred for 2 h. It was then washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (CH2Cl2) afforded tert-butyl 2-(nicotinamido)ethylcarbamate (3.1 g, 74%).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)Cl.[OH-].[Na+]>O>[C:1]([N:5]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:6][C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)N(NC(=O)c1ccc(Cl)cc1)C(=O)c1ccccc1
Temperature: 5 °C
Yield: 91 %

Procedure:
To a 5 L round bottom flask, equipped with a mechanical stirrer, containing the 571 g of wet N'-tert-butyl-N-(4-chlorobenzoyl)hydrazine intermediate and equipped with a 500 mL addition funnel containing 371 g of benzoyl chloride, is charged 1500 mL of methylene chloride, 250 mL of water and lastly 223 g of 50% by weight aqueous sodium hydroxide. The flask contents are stirred and cooled to 5° C. and the benzoyl chloride is added dropwise during a one hour period so that the temperature of the flask contents does not exceed 10° C. After allowing the flask contents to warm to room temperature, stirring is stopped and the organic and aqueous phases are allowed to separate overnight. The upper aqueous phase is removed by suction and is replaced by 500 mL of fresh water, the heterogeneous mixture is stirred, the phases are allowed to separate and the upper aqueous phase again is removed by suction. This washing procedure is repeated two more times and then 500-800 mL of hexane is added to the organic remainder. The contents are briefly stirred and then are poured onto a glass flitted Buchner funnel. The filter cake is washed extensively with a total of 2 L of hexane followed by 10 L of water and then is dried in vacuo at 65° C. for two days to give 758.2 g of N'-tert-butyl-N-(4-chlorobenzoyl)-N'-benzoylhydrazine as a white powder melting at 197°-198° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:12])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].[CH3:13][Si](C=[N+]=[N-])(C)C>CO.O1CCCC1>[NH2:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH3:13])=[O:8]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1ccc(C(=O)O)c(N)c1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)cc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-methoxyanthranilic acid (5.0 g, 30.0 mmol) in a mixture of 10% methanol in tetrahydrofuran (100 mL) was added dropwise (trimethylsilyl)diazomethane (2.0 M solution in diethyl ether, 18.0 mL, 36.0 mmol) at 0° C. The reaction mixture was stirred for 16 hours at room temperature then quenched by the addition of glacial acetic acid (0.1 mL). The reaction mixture was concentrated and the residue was partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (250 mL). The organic layer was separated and washed with water (50 mL), saturated sodium bicarbonate (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated to give methyl 2-amino-4-methoxybenzoate as an oil (5.4 g, quantitative). MS (EI) for C9H11NO3: 182 (MH+).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=1[Cl:40]>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[Cl:40])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2c(ccn2Cc2ccc(F)cc2Cl)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 1-(bromomethyl)-2-chloro-4-fluorobenzene. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50-7.43 (m, 1 H), 7.25-7.15 (m, 2 H), 7.13-7.06 (m, 2 H), 6.97-6.88 (m, 2 H), 6.29 (dd, J=3.5, 11.7 Hz, 1 H), 5.70-5.63 (m, 1 H), 5.61-5.51 (m, 2 H), 4.32-4.26 (m, 2 H), 2.96-2.80 (m, 2 H), 2.74 (s, 3 H), 2.16-2.04 (m, 2 H), 1.02-0.91 (s, 9H); LC/MS (m/z) ES+=537.33 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[CH3:10][S:11]([O-:13])=[O:12].[Na+].CNCCNC.O>CS(C)=O>[CH3:8][C:6]1[C:5]([NH2:9])=[CH:4][CH:3]=[C:2]([S:11]([CH3:10])(=[O:13])=[O:12])[N:7]=1
Reactant: CS(=O)[O-]
Reactant: Cc1nc(Br)ccc1N
Agent: CNCCNC
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(S(C)(=O)=O)ccc1N
Temperature: 150 °C
Yield: 60.2 %

Procedure:
A mixture of 6-bromo-2-methylpyridin-3-amine (40.0 g, 214 mmol), sodium methanesulfinate (87.3 g, 855 mmol), copper(I)trifluoromethanesulfonate-benzene complex (10.8 g, 21.4 mmol), and N1,N2-dimethylethane-1,2-diamine(10.8 g, 21.4 mmol) in DMSO (300 mL) was heated at 150° C. for four hours, cooled, and H2O (100 mL) was added. The dark brown solution was extracted with ethyl acetate (6×30 mL). The organic layer was washed with H2O (100 mL) to remove DMSO. The aqueous layer was back extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over Na2SO4, and filtered. After the volume of the filtrate was reduced to about 200 mL under reduced pressure, a solid product was precipitated and collected by filtration to give the title compound (24.0 g, 60%) as a brown powder. Exact mass calculated for C7H10N2O2S: 186.1. Found: LCMS m/z=187.1 (M+H+); 1H NMR (400 MHz, CDCl3) δ 2.44 (s, 3H), 3.13 (s, 3H), 4.66 (bs, 2H), 7.01 (d, J=8.34 Hz, 1H), 7.71 (d, J=8.34 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:10]([CH3:13])([O-:12])=[O:11].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:13][N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccccc1Cl
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])C=Cc1ccccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
Using an analogous reaction procedure and workup as described in Example 1, step 1, 2-chloro-benzaldehyde (5 g, 35.7142 mmol) in ethanol (161 mL) was reacted with nitro methane (1.93 mL, 35.7142 mmol) and 10N NaOH (1.35 g, 33.9607 mmol). The resulting mixture was stirred at 0° C. for 1 hr to afford 4.5 g of the product (75.73% yield).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH:16]([S:17]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:19])=[O:18])=[CH2:15]
Reactant: C1CCNCC1
Reactant: O=S(=O)(Cl)CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (683 mg, 6.75 mmol) is added to a solution of piperidine (274 mg, 3.22 mmol) and 2-chloroethanesulfonyl chloride (500 mg, 3.07 mmol) in dichloromethane (8 mL). The reaction is stirred for 2 h at room temperature. The reaction is diluted with ethyl acetate, sat. sodium bicarbonate solution is added. The organic layer is washed with brine and dried with MgSO4. The solvents is removed under vacuum to afford crude 1-(vinylsulfonyl)piperidine which is used directly in the next step without further purification. HPLC-MS calculated for C7H14NO2S (M+H+) 176.0, found 176.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[NH:13][C:12]([C:19]([O:21]C)=[O:20])=[CH:11]2.[OH-].[Na+]>CC(C)=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[NH:13][C:12]([C:19]([OH:21])=[O:20])=[CH:11]2
Reactant: COC(=O)c1cc2cc(OCc3cc(OC)c(OC)c(OC)c3)c(OC)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: COc1cc2[nH]c(C(=O)O)cc2cc1OCc1cc(OC)c(OC)c(OC)c1

Procedure:
180 mg of methyl 5-(3,4,5-trimethoxybenzyloxy)-6-methoxy-1H-indole-2-carboxylate are dissolved in 15 ml of acetone and 3 ml of methanol. 15 ml of 1N sodium hydroxide are added and the mixture is left to react for 2 hours at 30° C. The solvents are evaporated off under vacuum and the residual aqueous phase is acidified to pH 2 with concentrated hydrochloric acid. A solid is obtained, which is purified by taking it up in ethyl acetate at room temperature.
Reaction SMILES: [F:1][C:2]([C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].CN(C=O)C.[Br:27]N1C(=O)CCC1=O>O>[Br:27][C:16]1[CH:17]=[C:11]([C:2]([F:1])([C:3]([F:6])([F:5])[F:4])[C:7]([F:10])([F:9])[F:8])[CH:12]=[C:13]([C:18]([F:19])([F:20])[F:21])[C:14]=1[NH2:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
100 g (0.273 mol) of 4-(heptafluoropropan-2-yl)-2-(trifluoromethyl)aniline was charged to 500 ml of DMF, and 52.1 g (0.287 mol) of N-bromosuccinimide was charged in separate portions thereto over 30 minutes. After stirring at 60° C. for 2 hours, and then cooling to room temperature, the mixture was discharged to 2000 ml of water. The mixture was extracted with ethyl acetate, then washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=20:1) to prepare 89.0 g (yield 80%) of a target compound.